Annual assessments are needed to estimate influenza vaccine effectiveness (VE) for preventing medically-attended, laboratory-confirmed influenza illness. We have conducted these studies in Wisconsin since the 2004-05 season, and we propose to continue this work. Each season, we will establish a study cohort of individuals who are recommended to receive influenza vaccination based on age group or high risk medical condition. Influenza vaccination status will be determined by a real-time, internet-based immunization registry used by all public and private immunization providers serving the population. Members of the study cohort will be actively recruited for influenza testing during or after an inpatient or outpatient medical encounter for acute respiratory illness of <8 days duration. Patients with symptoms of feverishness, chills, or cough will be eligible. Research coordinators will identify and recruit eligible cohort members in primary care clinics, urgent care, and inpatient hospital wards. Ill patients who are not approached during a clinical encounter will be identified on the following day using electronic diagnosis codes and recruited. Nasopharyngeal and nasal swabs will be tested for influenza A and B virus using cell culture and RT-PCR. A case of influenza will be defined as an acute respiratory or febrile illness with documentation of influenza infection by culture or RT-PCR. Estimates of VE will be computed as 100 x (1 - RR), where RR is a measure of the relative risk of laboratory-confirmed influenza in the vaccinated versus unvaccinated patients who are enrolled and tested. For the case-control analysis, controls will include enrolled patients with a negative influenza culture and RT-PCR result (test-negative controls). RR will be derived from a Poisson regression model with robust variance estimation to account for multiple enrollments per patient. The regression models will adjust for high risk status, week of enrollment, and age. A mid-season interim analysis of VE will be performed after 50 laboratory- confirmed cases have been identified. The final analyses will include separate estimates of VE for children 6-59 months old, adults 65 years old, and healthy individuals 5 to 49 years old. All influenza isolates will be submitted to CDC for antigenic characterization, and we will assess the relationship between VE and antigenic match each season. To meet optional Objective 5 in the RFP, we will recruit a stratified random sample of elderly, non-institutionalized cohort members (65 years old) for collection of blood samples before vaccination and 3 to 6 weeks post-vaccination. Paired serum and PBMCs will be provided to CDC or a designated reference laboratory for antibody titers and measures of cell-mediated immunity.